Diffusion tensor imaging of the substantia nigra in Parkinson’s disease revisited
Jason Langley1, Daniel E Huddleston2, Michael Merritt1, Xiangchuan Chen1, Rebecca McMurray2, Michael Silver2, Stewart A Factor2, and Xiaoping Hu1

1Department of Biomedical Engineering, Emory University & Georgia Tech, Atlanta, GA, United States, 2Department of Neurology, Emory University, Atlanta, GA, United States

Synopsis

Inconclusive results from prior diffusion tensor imaging-based studies can be attributed to variability in location of regions of interest used to define the substantia nigra and its subcomponents. We apply recent findings from neuromelanin sensitive MRI to standardize regions of interest for the substantia nigra. Differences in fractional anisotropy and mean diffusivity were found in the neuromelanin sensitive substantia nigra but not in the substantia nigra defined in the b0 image.

Introduction

Multiple studies have investigated Parkinson’s disease (PD) related changes in fractional anisotropy (FA) and mean diffusivity (MD) in the substantia nigra (SN). While some of these studies revealed lower FA in the SN for PD groups1-4, others did not find differences in FA between PD and controls in the SN regions of interest (ROIs)5-7. The discrepancy can be attributed to variability in the anatomic location of ROIs used to define the SN across studies. In those studies, ROIs manually drawn on T2 weighted (T2w) spin echo images could be highly subjective and variable. This variability has been a confounding factor in identifying potential PD biomarkers from DTI metrics (illustrated in Figure 1)7.

In addition, recent work has shown that the SN seen in T2w and neuromelanin sensitive MRI (NM-MRI) contrasts are spatially incongruent8 and this incongruence could account for the wide range of results in previous studies (Figure 2)1-7. In the present work, we remove the ROI variability in previous studies by creating standardized SN pars compacta (SNpc) ROIs, defined in NM-MRI and SWI images from healthy controls and denoted NM-MRI SNpc ROI and T2w SN ROI, respectively. These ROIs are then used to investigate alterations in diffusion measures, namely MD and FA, due to PD.

Methods

A cohort of 37 subjects, who provided written, IRB-approved, informed consent, were studied. Demographic data for the cohort is summarized in Table 1.

All data were acquired on two 3 T MRI scanners (TRIO, Siemens Medical Solutions, Malvern, PA) at Emory University using a 12 channel receive only coil. Images from an MP-RAGE sequence (echo time (TE)/repetition time (TR)/inversion time=3.02/2600/800 ms, flip angle=8°, voxel size=1.0×1.0×1.0 mm3) were used for registration from subject space to common space. Diffusion MRI data were collected with a single-shot spin-echo, EPI sequence. Diffusion-weighting gradients were applied in 64 directions with a b value of 1000 s/mm2; TE/TR=97/3292 ms, FOV=212×212 mm2, matrix size of 106×106, voxel size=2×2×2 mm3, 64 slices with no gap, covering the entire brain. Two sets of diffusion-weighted images, with phase-encoding directions of opposite polarity, were acquired to correct for susceptibility distortion9. For each diffusion-weighted acquisition, six images without diffusion weighting (b0 images) were also acquired. The processing pipeline for DTI and common space registration are shown in Figure 3. Standard space NM-MRI SNpc and T2w ROIs from literature8 were used as ROIs for the NM-MRI SNpc ROI and T2 SN ROI, respectively.

Results

Mean FA values for the NM-MRI SNpc ROI were lower in the PD group than the control group (p=0.001). In contrast, no statistically significant difference in mean FA was seen in the T2w SN ROI (p=0.36). In addition, the average mean diffusivity (MD) offered no statistically significant difference between the two groups in the SN for the T2w SN ROI (p=0.43), while a statistically significant difference was seen in mean MD between PD and control groups for the NM-MRI SNpc ROI(p=0.01). These results are summarized in Figure 4.

The side more affected by PD in each subject by determined by comparing the lateralized sums of UPDRS-III subscores. In the SN volume contralateral to the more affected side, the PD group showed lower FA than the control group (PD: 0.36±0.03; CO: 0.41±0.03; p<10-4). In addition, a lateralized SN degeneration in the NM-MRI SNpc ROI consistent with the disease laterality was seen. Specifically, greater disease effects were seen in the FA in the rostral portion of the SN on the side contralateral to the more affected than the other side (p=0.03).

Discussion

The inconsistency in iron deposition as well as the location and volume of SN ROI, as shown in the b0 map, could explain the discrepancy between studies showing significant changes in the SN from PD [1-4] and those that found no difference in the SN [5-7]. All DTI-based studies [1-7] used a similar definition for SN ROIs [4]. In controls, we found little overlap in the hypointense region in the b0 map and the NM-MRI SNpc ROI, consistent with a recent report that found the overlap between the NM-MRI SNpc ROI and the T2w hypointense SN ROI to be ~10% in normal subjects [8]. PD patients with less iron deposition and less overlap between NM-MRI SNpc and T2w hypointense SN ROIs could appear to have a smaller disease effect on DTI measures as the ROIs would primarily be placed in the T2w SN ROI, which was found to exhibit no disease-related changes in DTI.

Acknowledgements

This work was partially supported by the Michael J. Fox Foundation (MJF 10854) and NINDS Parkinson's Disease Biomarkers Program U18 Award (U18 NS082143).

References

1. Chan, LL, et al. J Neurol Neurosurg Psychiatry 2007; 78(12):1383-6.

2. Du G, et al. Mov Disord 2011; 26(9): 1627-32.

3. Peran P, et al. Brain 2010; 133(11): 3423-33

4. Vaillancourt DE, et al. Neurology 2009; 72(16): 1378-84.

5. Aquino D, et al. Neurol Sci 2014; 35(5): 753-8.

6. Menke RA, et al. NeuroImage 2009; 47(2): 435-41.

7. Schwarz ST, et al. Neuroimage Clin 2013; 3: 481-8.

8. Langley J, et al. NeuroImage 2015; 112(1): 7-13

9. Andersson JL, et al. NeuroImage 2003; 20(2): 870-88

Figures

Figure 1.Slices placed four mm (two slices) below the red nucleus. The hypointense SN for the first subject is shown in (A) with the NM-MRI SN (shown in blue) overlaid(B). The hypointense SN for the second subject is shown in (C) with the NM-MRI SN (shown in blue) overlaid(D).

Figure 2.Comparison of the spatial locations of the T2w SN volume (red) and NM-MRI SN volume (blue). Sagittal view of the brainstem from the b0 map is shown in (A). Axial views of the SN are shown in(B&D). The SN volumes overlaid on the axial images are shown in(C&E).

Figure 3. Schematics illustrating the preprocessing procedure for DTI data (A) and registration from MNI to individual T1 space (B).

Figure 4. (A&B) Box plots showing mean FA for PD and CO groups in NM-MRI and T2w SN volumes.(C&D) display box plots showing mean MD in NM and T2w SN volumes for PD and CO groups. In(A&C), * and ** denote significance at the p=0.05 and p=0.001 levels.

Table 1. Demographic data for Parkinson’s and control groups.



Proc. Intl. Soc. Mag. Reson. Med. 24 (2016)
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